Mammary Gland Involution Provides a Unique Model to Study the TGF-β Cancer Paradox

Guo, Qiuchen; Betts, Courtney B.; Pennock, Nathan D.; Mitchell, Elizabeth; Schedin, Pepper

doi:10.3390/jcm6010010

Cited by 28 publications

(22 citation statements)

References 126 publications

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“…Because the level of the anti-tumour response of the host organism might depend on the size of the primary tumour, we inoculated two different numbers of mammary cancer cells (low density of 1 × 10 4 or high density of 1 × 10 6 cells per inoculation site) but no difference was observed. Such a finding is in apparent contradiction to what were reported by previous studies [ 39 , 40 ], but may be due to the specific mammary gland microenvironment [ 48 ], as compared to the subcutaneous or colic environments, or to specific anti-immune responses induced by 4T1 cells. Such possibilities should be investigated in further studies.…”

Section: Discussioncontrasting

confidence: 99%

P2X7 Receptor Promotes Mouse Mammary Cancer Cell Invasiveness and Tumour Progression, and Is a Target for Anticancer Treatment

Brisson

Chadet

Lopez‐Charcas

et al. 2020

Cancers

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The P2X7 receptor is an ATP-gated cation channel with a still ambiguous role in cancer progression, proposed to be either pro- or anti-cancerous, depending on the cancer or cell type in the tumour. Its role in mammary cancer progression is not yet defined. Here, we show that P2X7 receptor is functional in highly aggressive mammary cancer cells, and induces a change in cell morphology with fast F-actin reorganization and formation of filopodia, and promotes cancer cell invasiveness through both 2- and 3-dimensional extracellular matrices in vitro. Furthermore, P2X7 receptor sustains Cdc42 activity and the acquisition of a mesenchymal phenotype. In an immunocompetent mouse mammary cancer model, we reveal that the expression of P2X7 receptor in cancer cells, but not in the host mice, promotes tumour growth and metastasis development, which were reduced by treatment with specific P2X7 antagonists. Our results demonstrate that P2X7 receptor drives mammary tumour progression and represents a pertinent target for mammary cancer treatment.

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Section: Discussioncontrasting

confidence: 99%

P2X7 Receptor Promotes Mouse Mammary Cancer Cell Invasiveness and Tumour Progression, and Is a Target for Anticancer Treatment

Brisson

Chadet

Lopez‐Charcas

et al. 2020

Cancers

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show abstract

“…Cxcl12 is a stromal chemokine that attracts leukocytes through CXCR4 67 and enhances cell adhesion and survival through ACKR3 68 , these receptors are expressed in T/B cells and iCAFs, respectively. Interestingly, involuting mammary fibroblasts that highly express Cxcl12 induce monocyte recruitment and are associated with blockade of CD8+ T cell tumor infiltration 69 . Cxcl12 is also a known recruitment factor for MDSCs 52 .…”

Section: Discussionmentioning

confidence: 99%

Single cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype

Valdés-Mora

Salomon

Gloss

et al. 2019

Preprint

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Both luminal and basal breast cancer subtypes originate in the mammary luminal progenitor cell compartment. Basal breast cancer is associated with younger age, early relapse, and high mortality rate. Here we used unbiased droplet-based single-cell RNAseq to elucidate the cellular basis of tumour progression during the specification of the basal breast cancer subtype from the luminal progenitor population. Basal-like cancer cells resembled the alveolar lineage that is specified upon pregnancy and showed molecular features indicative of an interaction with the tumour microenvironment (TME) including EMT, hypoxia, lactation and involution. Involution signatures in luminal breast cancer tumours with alveolar lineage features were associated with worse prognosis and features of basal breast cancer. Our highresolution molecular characterisation of the tumour ecosystem also revealed a highly interactive cell-cell network reminiscent of an involution process. This involution mimicry involves malignant education of cancer-associated fibroblasts and myeloid cell recruitment to support tissue remodelling and sustained inflammation. Our study shows how luminal breast cancer acquires a post-lactation developmental program to shift molecular subtype and promote tumour progression, with potential to explain the increased risk of cancer during the post-partum period.

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“…During the involution process, programmed cell death eliminates~80-90% of the secretory mammary epithelium within a tissue microenvironment skewed towards wound healing 11,[13][14][15]20,21 . Specifically, studies show that postweaning mammary glands have increased lymphangiogenesis 11,22 , fibroblast activation 23,24 , fibrillar extracellular matrix deposition 25 , and enrichment for CD11b+/F480+ myeloid-derived suppressor cells (MDSCs), M2-skewed macrophages 21,26 , and Th-17, Th-2, and Treg skewed T-cells 27 compared to nulliparous glands.…”

Section: Introductionmentioning

confidence: 99%

Characterization of weaning-induced breast involution in women: implications for young women’s breast cancer

et al. 2020

Self Cite

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In rodents, weaning-induced mammary gland involution supports increased mammary tumor incidence, growth, and progression to metastasis. Further, the protumor attributes of gland involution are COX-2 dependent and mitigated by short-duration non-steroidal anti-inflammatory drugs (NSAIDs), suggesting a potential prevention strategy. However, the transition from lactation to postweaning breast involution has not been rigorously evaluated in healthy women. Here we queried breast biopsies from healthy women (n = 112) obtained at nulliparity, lactation, and multiple postweaning time points using quantitative immunohistochemistry. We found that mammary remodeling programs observed in rodents are mirrored in the human breast. Specifically, lactation associates with the expansion of large, secretory mammary lobules and weaning associates with lobule loss concurrent with epithelial cell death and stromal hallmarks of wound healing, including COX-2 upregulation. Altogether, our data demonstrate that weaning-induced breast involution occurs rapidly, concurrent with protumor-like attributes, and is a potential target for NSAID-based breast cancer prevention.

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Mammary Gland Involution Provides a Unique Model to Study the TGF-β Cancer Paradox

Cited by 28 publications

References 126 publications

P2X7 Receptor Promotes Mouse Mammary Cancer Cell Invasiveness and Tumour Progression, and Is a Target for Anticancer Treatment

P2X7 Receptor Promotes Mouse Mammary Cancer Cell Invasiveness and Tumour Progression, and Is a Target for Anticancer Treatment

Single cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype

Characterization of weaning-induced breast involution in women: implications for young women’s breast cancer

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